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Induction of endoplasmic reticulum stress by ellipticine plant alkaloids

Maria Hägg1, Maria Berndtsson, Aleksandra Mandic

  • 1Department of Oncology and Pathology, Cancer Center Karolinska, Karolinska Institute and Hospital, Stockholm, Sweden.

Molecular Cancer Therapeutics
|April 14, 2004
PubMed

Insights

The plant alkaloid 6-propanamine ellipticine (6-PA-ELL) triggers apoptosis in breast cancer cells by inducing endoplasmic reticulum stress and Bak activation. This compound

Area of Science:

  • Pharmacology and Toxicology
  • Cancer Biology
  • Cellular Stress Responses

Background:

  • Anticancer drugs exhibit complex mechanisms affecting multiple cellular targets.
  • Understanding drug-induced cytotoxicity is crucial for cancer therapy.
  • Ellipticines are cytotoxic plant alkaloids that inhibit topoisomerase II.

Purpose of the Study:

  • To investigate the apoptotic mechanisms of ellipticines, focusing on endoplasmic reticulum (ER) stress.
  • To elucidate the role of Bak and ER stress in 6-propanamine ellipticine (6-PA-ELL)-induced cytotoxicity.
  • To explore the correlation between ellipticine derivatives' pro-apoptotic activity and ER stress induction.

Main Methods:

  • Apoptosis assays in MDA-MB-231 breast cancer cells and Bak-knockout mouse embryo fibroblasts.
  • Analysis of Bak conformational change, cytochrome c release, and caspase-12 activation.
  • Measurement of GRP78/BiP and GRP94 expression, and XBP1 mRNA splicing.
  • Studies in enucleated cells to identify cytoplasmic targets.

Main Results:

  • 6-PA-ELL rapidly induced apoptosis, Bak conformational change, and cytochrome c release.
  • Bak was critical for 6-PA-ELL-induced cytotoxicity.
  • 6-PA-ELL increased GRP78/BiP and GRP94 expression, indicating ER stress.
  • ER stress induction correlated with the pro-apoptotic activity of ellipticine derivatives.
  • 6-PA-ELL induced XBP1 splicing and caspase-12 activation, and apoptotic signaling in enucleated cells.

Conclusions:

  • 6-PA-ELL induces apoptosis in breast cancer cells through Bak activation and ER stress.
  • ER stress contributes significantly to the cytotoxic effects of ellipticines.
  • Ellipticine derivatives' pro-apoptotic potential is linked to their ability to induce ER stress.

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